RESUMEN
BACKGROUND: Celecoxib, an anti-inflammatory drug, combined therapies using antimicrobials and immune modulator drugs are being studied. OBJECTIVE: To assess whether Celecoxib has direct in vitro antifungal effect against the Paracoccidioides brasiliensis, the causative agent of Paracoccidioidomycosis-(PCM) and also if it improves the in vivo activity of neutrophils-(PMN) in an experimental murine subcutaneous-(air pouch) model of the disease. METHODS: The antifungal activity of Celecoxib(6 mg/mL) on P. brasiliensis-(Pb18) was evaluated using the microdilution technique. Splenocytes co-cultured with Pb18 and treated with Celecoxib(6 mg/mL) were co-cultured for 24, 48 and 72-hours. Swiss mice were inoculated with Pb18 and treated with Celecoxib(6 mg/kg) in the subcutaneous air pouch. Neutrophils were collected from the air pouch. Mitochondrial activity, reactive oxygen production, catalase, peroxidase, cytokines and chemokines, nitrogen species, total protein, microbicidal activity of PMNs and viable Pb18 cells numbers were analyzed. RESULTS: Celecoxib had no cytotoxic effect on splenocytes co-cultured with Pb18, but had a marked direct antifungal effect, inhibiting fungal growth both in vitro and in vivo. Celecoxib interaction with immune system cells in the air pouch, it leads to activation of PMNs, as confirmed by several parameters (mitochondrial activity, reactive oxygen species, peroxidase, KC and IL-6 increase, killing constant and phagocytosis). Celecoxib was able to reduce IL-4, IL-10 and IL-12 cytokine production. The number of recovered viable Pb18 decreased dramatically. CONCLUSIONS: This is the first report of the direct antifungal activity of Celecoxib against P. brasiliensis. The use of Celecoxib opens a new possibility for future treatment of PCM.
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Antifúngicos , Celecoxib , Neutrófilos , Paracoccidioides , Paracoccidioidomicosis , Animales , Paracoccidioides/efectos de los fármacos , Paracoccidioides/inmunología , Ratones , Celecoxib/farmacología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Paracoccidioidomicosis/tratamiento farmacológico , Paracoccidioidomicosis/inmunología , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Citocinas/metabolismo , Células Cultivadas , Masculino , Bazo/inmunología , Bazo/citología , Bazo/efectos de los fármacos , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Breast cancer is a major global health issue, causing high incidence and mortality rates as well as psychological stress for patients. Chemotherapy resistance is a common challenge, and the Aldo-keto reductase family one-member C3 enzyme is associated with resistance to anthracyclines like doxorubicin. Recent studies have identified celecoxib as a potential treatment for breast cancer. Virtual screening was conducted using a quantitative structure-activity relationship model to develop similar drugs; this involved backpropagation of artificial neural networks and structure-based virtual screening. The screening revealed that the C-6 molecule had a higher affinity for the enzyme (-11.4 kcal/mol), a lower half-maximal inhibitory concentration value (1.7 µM), and a safer toxicological profile than celecoxib. The compound C-6 was synthesized with an 82% yield, and its biological activity was evaluated. The results showed that C-6 had a more substantial cytotoxic effect on MCF-7 cells (62%) compared to DOX (63%) and celecoxib (79.5%). Additionally, C-6 had a less harmful impact on healthy L929 cells than DOX and celecoxib. These findings suggest that C-6 has promising potential as a breast cancer treatment.
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Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas , Antiinflamatorios no Esteroideos , Neoplasias de la Mama , Diseño de Fármacos , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Células MCF-7 , Diseño Asistido por Computadora , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad Cuantitativa , Simulación del Acoplamiento Molecular , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Celecoxib/farmacología , Celecoxib/química , Proliferación Celular/efectos de los fármacosRESUMEN
Depression and anxiety disorders have their pathophysiologies linked to inflammation and oxidative stress. In this context, celecoxib (CLX) and etoricoxib (ETR) inhibit cyclooxygenase 2 (COX-2), an enzyme expressed by cells involved in the inflammatory process and found in the brain. Studies have been using CLX as a possible drug in the treatment of depression, although its mechanisms at the central nervous system level are not fully elucidated. In this study, the effects of CLX and ETR on behavioral, oxidative, and inflammatory changes induced by systemic exposure to Escherichia coli lipopolysaccharide (LPS) were evaluated in adult male swiss mice. For ten days, the animals received intraperitoneal injections of LPS at 0.5 mg/kg. From the sixth to the tenth day, one hour after LPS exposure, they were treated orally with CLX (15 mg/kg), ETR (10 mg/kg), or fluoxetine (FLU) (20 mg/kg). Twenty-four hours after the last oral administration, the animals underwent evaluation of locomotor activity (open field test), predictive tests for depressive-like behavior (forced swim and tail suspension tests), and anxiolytic-like effect (elevated plus maze and hole board tests). Subsequently, the hippocampus, prefrontal cortex and striatum were dissected for the measurement of oxidative and nitrosative parameters (malondialdehyde, nitrite, and glutathione) and quantification of pro-inflammatory cytokines (IL-1ß and IL-6). LPS induced depressive and anxious-like behavior, and treatment with CLX or ETR was able to reverse most of the behavioral changes. It was evidenced that nitrosative stress and the degree of lipid peroxidation induced by LPS were reduced in different brain areas after treatment with the drugs, as well as the endogenous defense system against free radicals was strengthened. CLX and ETR also significantly reduced LPS-induced cytokine levels. These data are expected to expand information on the role of inflammation in depression and anxiety and provide insights into possible mechanisms of COX-2 inhibitors in psychiatric disorders with a neurobiological basis in inflammation and oxidative stress.
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Ansiedad , Conducta Animal , Celecoxib , Inhibidores de la Ciclooxigenasa 2 , Depresión , Lipopolisacáridos , Estrés Oxidativo , Animales , Masculino , Ratones , Lipopolisacáridos/farmacología , Estrés Oxidativo/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Depresión/tratamiento farmacológico , Depresión/inducido químicamente , Depresión/metabolismo , Ansiedad/tratamiento farmacológico , Ansiedad/inducido químicamente , Conducta Animal/efectos de los fármacos , Celecoxib/farmacología , Celecoxib/administración & dosificación , Etoricoxib/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/metabolismoRESUMEN
Pulmonary tuberculosis (TB) inflammation is an underestimated disease complication which anti-inflammatory drugs may alleviate. This study explored the potential use of the COX-2 inhibitors acetylsalicylic acid (ASA) and celecoxib in 12 TB patients and 12 healthy controls using a whole-blood ex vivo model where TNFα, PGE2, and LTB4 plasma levels were quantitated by ELISA; we also measured COX-2, 5-LOX, 12-LOX, and 15-LOX gene expression. We observed a significant TNFα production in response to stimulation with LPS or M. tuberculosis (Mtb). Celecoxib, but not ASA, reduced TNFα and PGE2 production, while increasing LTB4 in patients after infection with Mtb. Gene expression of COX-2 and 5-LOX was higher in controls, while 12-LOX was significantly higher in patients. 15-LOX expression was similar in both groups. We concluded that COX-2 inhibitors downregulate inflammation after Mtb infection, and our methodology offers a straightforward time-efficient approach for evaluating different drugs in this context. Further research is warranted to elucidate the underlying mechanisms and assess the potential clinical benefit.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Celecoxib/farmacología , Celecoxib/uso terapéutico , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Dinoprostona , Inmunidad , Inflamación/metabolismo , Leucotrieno B4/metabolismo , Mycobacterium tuberculosis/metabolismo , Tuberculosis/tratamiento farmacológico , Factor de Necrosis Tumoral alfaRESUMEN
Drug combinations are increasingly studied in the field of anticancer agents. Mathematical models, such as Loewe, Bliss, and HSA, are used to interpret drug combinations, while informatics tools help cancer researchers identify the most effective combinations. However, the different algorithms each software uses lead to results that do not always correlate. This study compared the performance of Combenefit (Ver. 2.021) and SynergyFinder (Ver. 3.6) in analyzing drug synergy by studying combinations involving non-steroidal analgesics (celecoxib and indomethacin) and antitumor drugs (carboplatin, gemcitabine, and vinorelbine) on two canine mammary tumor cell lines. The drugs were characterized, their optimal concentration-response ranges were determined, and nine concentrations of each drug were used to make combination matrices. Viability data were analyzed under the HSA, Loewe, and Bliss models. Celecoxib-based combinations showed the most consistent synergistic effect among software and reference models. Combination heatmaps revealed that Combenefit gave stronger synergy signals, while SynergyFinder produced better concentration-response fitting. When the average values of the combination matrices were compared, some combinations shifted from synergistic to antagonistic due to differences in the curve fitting. We also used a simulated dataset to normalize each software's synergy scores, finding that Combenefit tends to increase the distance between synergistic and antagonistic combinations. We conclude that concentration-response data fitting biases the direction of the combination (synergistic or antagonistic). In contrast, the scoring from each software increases the differences among synergistic or antagonistic combinations in Combenefit when compared to SynergyFinder. We strongly recommend using multiple reference models and reporting complete data analysis for synergy claiming in combination studies.
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Antineoplásicos , Animales , Perros , Celecoxib/farmacología , Quimioterapia Combinada , Antineoplásicos/farmacología , Programas Informáticos , Combinación de Medicamentos , Sinergismo Farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologíaRESUMEN
Delayed cancer progression in the ventral prostate of the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model has been previously reported upon celecoxib and nintedanib co-administration. Herein, we sought to further investigate the effects of these drugs association in some of their direct molecular targets (COX-2, VEGF and VEGFR-2) and in reactive stroma markers (TGF-ß, αSMA, vimentin and pro-collagen 1) in the dorsolateral prostate, looking for lobe-specific responses. Male TRAMP mice were treated with celecoxib (10 mg/Kg, i.o.) and/or nintedanib (15 mg/Kg, i.o.) for 6 weeks and prostate was harvested for morphological and protein expression analyses. Results showed that combined therapy resulted in unique antitumor effects in dorsolateral prostate, especially due to the respective stromal or epithelial antiproliferative actions of these drugs, which altogether led to a complete inversion in high-grade (HGPIN) versus low-grade (LGPIN) premalignant lesion incidences in relation to controls. At the molecular level, this duality in drug action was paralleled by the differential down/upregulation of TGF-ß signaling by celecoxib/nintedanib, thus leading to associated changes in stroma composition towards regression or quiescence, respectively. Additionally, combined therapy was able to promote decreased expression of inflammatory (COX-2) and angiogenesis (VEGF/VEGFR-2) mediators. Overall, celecoxib and nintedanib association provided enhanced antitumor effects in TRAMP dorsolateral as compared to former registers in ventral prostate, thus demonstrating lobe-specific responses of this combined chemoprevention approach. Among these responses, we highlight the ability in promoting TGF-ß signaling and its associated stromal maturation/stabilization, thus yielding a more quiescent stromal milieu and resulting in greater epithelial proliferation impairment.
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Próstata , Neoplasias de la Próstata , Humanos , Ratones , Animales , Masculino , Celecoxib/farmacología , Celecoxib/uso terapéutico , Celecoxib/metabolismo , Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ratones Transgénicos , Ciclooxigenasa 2/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
The aim of this study was to explore the effects of nonsteroidal anti-inflammatory drugs on biomineralization of enamel. Sixty C57Bl6 male mice were used, which were assigned into three groups: celecoxib (n = 20) or indomethacin (n = 20) treatment for a period of 28 days or received no medication (control group, n = 20). Visual inspection and microcomputed tomography were used to analyze enamel morphology. Scanning electron microscopy-Energy dispersive X-ray and Knoop microhardness test were used to quantify chemical element content (Ca, P, C, O) and enamel microhardness, respectively. Tissues were collected to investigate the synthesis, activity or nuclear translocation of metalloproteinase-20, transcription factor Runx2, dentin sialoprotein and cyclooxygenase-2 enzyme by means of immunohistochemistry, in situ zymography and indirect immunofluorescence. Treatment with indomethacin and celecoxib reduced the Ca and P content, microhardness and mineral density in enamel. Treatment with nonsteroidal anti-inflammatory drugs caused an accumulation of metalloproteinase-20 and overall increased enzymatic activity in enamel matrix, while the synthesis of the transcription factor Runx2 was inhibited by these drugs. Interestingly, indomethacin inhibited Runx2 translocation to the nucleus whereas celecoxib did not. Those findings show that non-steroidal anti-inflammatory drugs impact the enamel biomineralization and could be involved in the etiology tooth enamel defects if used during the period of tooth formation and mineralization.
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Subunidad alfa 1 del Factor de Unión al Sitio Principal , Indometacina , Animales , Antiinflamatorios no Esteroideos/farmacología , Biomineralización , Celecoxib/farmacología , Ciclooxigenasa 2 , Indometacina/farmacología , Masculino , Ratones , Minerales , Microtomografía por Rayos XRESUMEN
PURPOSE: To evaluate the effect of a selective cyclooxygenase 2 (COX-2) inhibitor on trigeminal ganglion changes and orofacial discomfort/nociception in rats submitted to an experimental model of dental occlusal interference (DOI). METHODS: Female Wistar rats (180-200 g) were divided into five groups: a sham group (without DOI) (n=15); and four experimental groups with DOI treated daily with 0.1 mL/kg saline (DOI+SAL), 8, 16, or 32 mg/kg celecoxib (DOI+cel -8, -16, -32) (n=30/group). The animals were euthanized after one, three, and seven days. The bilateral trigeminal ganglia were analyzed histomorphometrically (neuron cell body area) and immunohistochemically (COX-2, nuclear factor-kappa B [NFkB], and peroxisome proliferator-activated receptor-y [PPARy]). A bilateral nociception assay of the masseter muscle was performed. The number of bites/scratches, weight, and grimace scale scores were determined daily. One-way/two-way analysis of variance (ANOVA)/Bonferroni post hoc tests were used (P < .05, GraphPad Prism 5.0). RESULTS: DOI+SAL showed a reduction in neuron cell body area bilaterally, whereas DOI+cel-32 exhibited a significative increase in neuron cell body area compared with DOI+SAL group (P < 0.05). The ipsilateral (P=0.007 and P=0.039) and contralateral (P < 0.001 and P=0.005) overexpression of COX-2 and NFkB and downregulation of PPARy (P=0.016 and P < 0.001) occurred in DOI+SAL, but DOI+cel-32 reverted this alteration. DOI+SAL showed increase in isplateral (P < 0.001) and contralateral (P < 0.001) nociception, an increased number of bites (P=0.010), scratches (P < 0.001), and grimace scores (P=0.032). In the group of DOI+cel-32, these parameters were reduced. CONCLUSIONS: Celecoxib attenuated DOI-induced transitory nociception/orofacial discomfort resulting from trigeminal COX-2 overexpression.
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Dolor Facial , Ganglio del Trigémino , Animales , Antiinflamatorios no Esteroideos/farmacología , Celecoxib/farmacología , Celecoxib/uso terapéutico , Ciclooxigenasa 2/farmacología , Oclusión Dental , Modelos Animales de Enfermedad , Dolor Facial/tratamiento farmacológico , Femenino , Ratas , Ratas WistarRESUMEN
This article aims at reviewing celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) predominantly has two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role related to homeostatic effects in renal and platelets, while the latter is mainly responsible for the induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and have no side effects. In this sense, celecoxib is the only potent, selective COX-2 inhibitor that is still commercially available (within the "coxib" family). Thus, celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for the COX-2 enzyme. This review provides inhibition highlights that should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs), which act as COX-2 inhibitors with lesser side effects on the human body.
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Celecoxib , Inhibidores de la Ciclooxigenasa 2 , Antiinflamatorios no Esteroideos/farmacología , Celecoxib/farmacología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2/farmacología , Humanos , IsoenzimasRESUMEN
Cyclooxygenase 2 (COX-2) is a well-established target for the design of anti-inflammatory intermediates. Celecoxib was selected as a template molecule to perform ligand-based virtual screening, i.e. to search for structures with similarity in shape and electrostatic potential, with a gradual increase in accuracy through the combined fitting of several steps using eight commercial databases. The molecules ZINC408709 and ZINC2090319 reproduced values within the limits established in an initial study of absorption and distribution in the body. No alert was fired for possible toxic groups when these molecules were subjected to toxicity prediction. Molecular docking results with these compounds showed a higher binding affinity in comparison to rofecoxib for the COX-2 target. Additionally, ZINC408709 and ZINC2090319 were predicted to be potentially biologically active. In in silico prediction of endocrine disruption potential, it was established that the molecule ZINC2090319 binds strongly to the target related to cardiovascular risk in a desirable way as a non-steroidal antagonist and ZINC408709 binds strongly to the target that is associated with the treatment of inflammatory pathologies and similar to celecoxib. Metabolites generated from these compounds are less likely to have side effects. Simulations were used to evaluate the interaction of compounds with COX-1 and COX-2 during 200 ns. Despite the differences, ZINC408709 molecule showed better stability for COX-2 during molecular dynamics simulation. In the calculations of free energy MM/PBSA, the molecule ZINC408709 ΔGbind value has a higher affinity to celecoxib and rofecoxib COX-2. This demonstrates that the selected substances can be considered as promising COX-2 inhibitors. Communicated by Ramaswamy H. Sarma.
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Inhibidores de la Ciclooxigenasa 2 , Simulación de Dinámica Molecular , Celecoxib/farmacología , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Ligandos , Simulación del Acoplamiento MolecularRESUMEN
This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors.
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Antiinflamatorios no Esteroideos/farmacología , Antiulcerosos/farmacología , Edema/tratamiento farmacológico , Peritonitis/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Úlcera/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiulcerosos/síntesis química , Antiulcerosos/química , Carragenina , Celecoxib/química , Celecoxib/farmacología , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Lignanos/química , Lignanos/farmacología , Masculino , Ratones , Estructura Molecular , Peritonitis/inducido químicamente , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Ratas , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología , Úlcera/inducido químicamenteRESUMEN
RESUMEN: La angiogénesis es el proceso de formación de vasos sanguíneos a partir de otros formados previamente. Existen varios factores que están involucrados en el proceso, así como agentes capaces de modular distintas etapas de esta. Si bien, se ha observado que Celecoxib es capaz de inhibir la angiogénesis en distintos modelos, aún no se ha observado la potencial capacidad antiangiogénica de este agente cuando es microencapsulado en PLGA. Se incubaron huevos fertilizados y a las 48 horas se dividieron en 4 grupos para ser instilados con PBS (control), PLGA, Celecoxib 1000 ppm o Celecoxib 1000 ppm + PLGA. Se realizó un conteo de los vasos sanguíneos a las 48, 72 y 96 horas post aplicación de la solución a estudiar. Los resultados muestran que tanto Celecoxib como Celecoxib+PLGA reducen los vasos sanguíneos, manteniendo el mismo efecto a las 48, 72 y 96 horas y no existen diferencias significativas entre los dos tratamientos. Esto podría ser explicado por la concentración de Celecoxib usada o el margen de tiempo analizado, pudiendo encontrarse diferencias posteriores a este rango de tiempo o con concentraciones distintas.
SUMMARY: Angiogenesis is the process of blood vessel formation from previously formed ones. There are several factors involved in the process, as well as agents capable of modulating different stages of it. Although, it has been observed that Celecoxib is capable of inhibiting angiogenesis in different models, the potential antiangiogenic capacity of this agent has not yet been observed when it is microencapsulated in PLGA. Fertilized eggs were incubated and at 48 hours they were divided into 4 groups to be instilled with PBS (control), PLGA, Celecoxib 1000ppm or Celecoxib 1000 ppm + PLGA. A blood vessel count was performed at 48, 72 and 96 hours after application of the solution to be studied. The results show that both Celecoxib and Celecoxib + PLGA reduce blood vessels, maintaining the same effect at 48, 72 and 96 hours and there are no significant differences between the two treatments. This could be explained by the concentration of Celecoxib used or the time frame analyzed, being able to find differences after this time range or with different concentrations.
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Inhibidores de la Angiogénesis/farmacología , Celecoxib/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , CápsulasRESUMEN
BACKGROUND: In this article, a series of 20 new thiosemicarbazone derivatives containing indole were synthesized and evaluated for their anti-inflammatory potential. METHODS: The compounds were obtained through a synthetic route of only two steps, with yields that varied between 33.6 and 90.4%, and characterized by spectroscopic and spectrometric techniques. RESULTS: An initial screening through the lymphoproliferation assay revealed that compounds LT76, LT81, and LT87 were able to inhibit lymphocyte proliferation, with CC50 of 0.56 ± 0.036, 0.9 ± 0.01 and 0.5 ± 0.07 µM, respectively, better results than indomethacin (CC50 > 12 µM). In addition, these compounds were able to suppress the in-vitro production of TNF-α and NO, in addition to stimulating the production of IL-4. Reinforcing in-vitro assays, the compounds were able to inhibit COX-2 similar to Celecoxib showing greater selectivity for this isoform (LT81 SI: 23.06 versus Celecoxib SI: 11.88). Animal studies showed that compounds LT76 (64.8% inhibition after 6 h), LT81 (89% inhibition after 6 h) and LT87 (100% inhibition after 4 h) were able to suppress edema in mice after inoculation carrageenan with greater potency than indomethacin, and immunohistochemistry revealed that the groups treated with LT76, LT81 and LT87 reduced the expression of COX-2, similar or better results when compared to indomethacin. Complementarily, in-silico studies have shown that these compounds have a good pharmacokinetic profile, for respecting the parameters of Lipinski and Veber, showing their good bioavailability. CONCLUSIONS: These results demonstrate the potency of thiosemicarbazone derivatives containing indole and confirm their importance as scaffolds of molecules with notorious anti-inflammatory activity.
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Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Tiosemicarbazonas/farmacología , Animales , Carragenina/farmacología , Celecoxib/farmacología , Proliferación Celular/efectos de los fármacos , Edema/tratamiento farmacológico , Edema/metabolismo , Indoles/farmacología , Indometacina/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
AIM: To evaluate the efficacy of selective and nonselective inhibitors of cyclooxygenase-2 enzymes in the treatment of experimental apical periodontitis induced by bacterial lipopolysaccharide (LPS) in vivo in a mouse model. METHODOLOGY: Thirty-six C57BL/6 mice were used. After access cavity preparation, a solution containing E. coli LPS (1.0 µg µL-1 ) was inoculated into the root canals of the mandibular and maxillary right first molars (n = 72) After 30 days, apical periodontitis was established and the animals were systemically treated with celecoxib, a selective COX-2 inhibitor (15 mg kg-1 ), or indomethacin, a nonselective COX-2 inhibitor (5 mg kg-1 ), for 7 and 14 days. Blocks containing teeth and bone were removed for histopathological and histometric analyses (haematoxylin and eosin), evaluation of osteoclasts numbers (tartrate-resistant acid phosphatase enzyme - TRAP) and immunohistochemistry for RANK, RANKL and OPG. Gene expression was performed using reverse transcription and real-time polymerase chain reaction (qRT-PCR) for RANK, RANKL, OPG, TRAP, MMP-9, cathepsin K and calcitonin receptor. Histopathological, histometric, TRAP, immunohistochemistry and qRT-PCR data were evaluated using Kruskal-Wallis followed by Dunn's test (α = 0.05). RESULTS: Systemic administration of celecoxib for 7 and 14 days prevented periapical bone resorption (P < 0.0001), differently from indomethacin that exacerbated bone resorption at 7 days (P < 0.0001) or exerted no effect at 14 days (P = 0.8488). Celecoxib treatment reduced osteoclast formation in apical periodontitis, regardless of the period of treatment (P < 0.0001 for 7 days and P = 0.026 for 14 days). Administration of celecoxib or indomethacin differentially modulated the expression of genes involved in bone resorption. At 7 days, celecoxib and indomethacin treatment significantly inhibited expression of mRNA for cathepsin K (P = 0.0005 and P = 0.016, respectively) without changing TRAP, MMP-9 and calcitonin receptor gene expression. At 14 days, celecoxib significantly inhibited expression of mRNA for MMP-9 (P < 0.0001) and calcitonin receptor (P = 0.004), whilst indomethacin exerted no effect on MMP-9 (P = 0.216) and calcitonin receptor (P = 0.971) but significantly augmented cathepsin K gene expression (P = 0.001). CONCLUSIONS: The selective COX-2 inhibitor celecoxib reduced osteoclastogenic signalling and activity that dampened bone resorption in LPS-induced apical periodontitis in mice, with greater efficacy than the nonselective inhibitor indomethacin.
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Resorción Ósea , Lipopolisacáridos , Animales , Resorción Ósea/tratamiento farmacológico , Celecoxib/farmacología , Celecoxib/uso terapéutico , Escherichia coli , Ratones , Ratones Endogámicos C57BL , Osteoclastos , Ligando RANKRESUMEN
Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side effects of non-selective inhibitors of COX-1. Thus, the present study aims to identify new selective chemical entities for the COX-2 enzyme via molecular modeling approaches. The best pharmacophore model was used to identify compounds within the ZINC database. The molecular properties were determined and selected with Pearson's correlation for the construction of quantitative structure-activity relationship (QSAR) models to predict the biological activities of the compounds obtained with virtual screening. The pharmacokinetic/toxicological profiles of the compounds were determined, as well as the binding modes through molecular docking compared to commercial compounds (rofecoxib and celecoxib). The QSAR analysis showed a fit with R = 0.9617, R2 = 0.9250, standard error of estimate (SEE) = 0.2238, and F = 46.2739, with the tetra-parametric regression model. After the analysis, only three promising inhibitors were selected, Z-964, Z-627, and Z-814, with their predicted pIC50 (-log IC50) values, Z-814 = 7.9484, Z-627 = 9.3458, and Z-964 = 9.5272. All candidates inhibitors complied with Lipinski's rule of five, which predicts a good oral availability and can be used in in vitro and in vivo tests in the zebrafish model in order to confirm the obtained in silico data.
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Inhibidores de la Ciclooxigenasa 2/farmacología , Inflamación/tratamiento farmacológico , Animales , Sitios de Unión , Células CACO-2 , Celecoxib/farmacología , Perros , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Lactonas/farmacología , Células de Riñón Canino Madin Darby , Simulación del Acoplamiento Molecular , Estructura Molecular , Permeabilidad , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Análisis de Regresión , Programas Informáticos , Sulfonas/farmacologíaRESUMEN
BACKGROUND/OBJECTIVES: 4-(Arylchalcogenyl)-1H-pyrazoles containing selenium or sulfur (0.001-50 mg/kg) were investigated regarding the intragastric route effect (ig) administration on nociception in mice. In this study, nociception and inflammation were induced by chemical agents such as formalin (0.92%), sodium L-glutamate 1-hydrate (20 µmol), croton oil (2.5%), acetic acid (1.6%) and thermic model with a hot plate test. RESULTS: Compounds 1a-c had the ability to reduce licking time in both phases (neurogenic and inflammatory) of the formalin test and glutamate. Only compounds 1a and 1b had the ability to reduce the number of abdominal writhes caused by acetic acid. The same was observed with the positive control celecoxib. To evaluate the possible anti-inflammatory activity of compounds 1a-c, the induction of paw edema by formalin and ear edema by croton oil was performed. For the inflammation induced by formalin, significant effects were observed from the dose of 0.1 mg/kg (1a-b) and 10 mg/kg (1c). In the ear edema test, it can be observed that only compound 1a had a significant effect. In the hotplate test, all the compounds had the ability to reduce the latency time. CONCLUSION: The results demonstrated that acute antinociceptive and anti-inflammatory effects of 4-(arylchalcogenyl)-1H-pyrazoles 1a is better than compared with the compound 1b and 1c in mice. This resulted in these molecules attracting the interest of researchers to perform future studies to develop new drugs to treat pain and inflammatory clinical conditions.
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Analgésicos/farmacología , Antiinflamatorios/farmacología , Pirazoles/farmacología , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Celecoxib/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Masculino , Ratones , Nocicepción/efectos de los fármacos , Dolor/tratamiento farmacológico , Pirazoles/administración & dosificación , Pirazoles/química , Selenio/química , Azufre/químicaRESUMEN
Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson's disease (PD). Pain is a prevalent PD's non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available. Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception. Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1). We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD. Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.
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Cannabidiol/farmacología , Nocicepción/efectos de los fármacos , Enfermedad de Parkinson/fisiopatología , Amidohidrolasas/antagonistas & inhibidores , Analgésicos/farmacología , Animales , Benzamidas/farmacología , Encéfalo/patología , Capsaicina/análogos & derivados , Capsaicina/farmacología , Carbamatos/farmacología , Celecoxib/farmacología , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/farmacología , Oxidopamina , Dolor/tratamiento farmacológico , Piperidinas/farmacología , Pirazoles/farmacología , Tienamicinas/farmacologíaRESUMEN
OBJECTIVES: Infection, inflammation and bone resorption are closely related events in apical periodontitis development. Therefore, we sought to investigate the role of cyclooxygenase (COX) in osteoclastogenesis and bone metabolism signaling in periapical bone tissue after bacterial lipopolysaccharide (LPS) inoculation into root canals. METHODOLOGY: Seventy two C57BL/6 mice had the root canals of the first molars inoculated with a solution containing LPS from E. coli (1.0 mg/mL) and received selective (celecoxib) or non-selective (indomethacin) COX-2 inhibitor. After 7, 14, 21 and 28 days the animals were euthanized and the tissues removed for total RNA extraction. Evaluation of gene expression was performed by qRT-PCR. Statistical analysis was performed using analysis of variance (ANOVA) followed by post-tests (α=0.05). RESULTS: LPS induced expression of mRNA for COX-2 (Ptgs2) and PGE2 receptors (Ptger1, Ptger3 and Ptger4), indicating that cyclooxygenase is involved in periapical response to LPS. A signaling that favours bone resorption was observed because Tnfsf11 (RANKL), Vegfa, Ctsk, Mmp9, Cd36, Icam, Vcam1, Nfkb1 and Sox9 were upregulated in response to LPS. Indomethacin and celecoxib differentially modulated expression of osteoclastogenic and other bone metabolism genes: celecoxib downregulated Igf1r, Ctsk, Mmp9, Cd36, Icam1, Nfkb1, Smad3, Sox9, Csf3, Vcam1 and Itga3 whereas indomethacin inhibited Tgfbr1, Igf1r, Ctsk, Mmp9, Sox9, Cd36 and Icam1. CONCLUSIONS: We demonstrated that gene expression for COX-2 and PGE2 receptors was upregulated after LPS inoculation into the root canals. Additionally, early administration of indomethacin and celecoxib (NSAIDs) inhibited osteoclastogenic signaling. The relevance of the cyclooxygenase pathway in apical periodontitis was shown by a wide modulation in the expression of genes involved in both bone catabolism and anabolism.
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Inhibidores de la Ciclooxigenasa/farmacología , Cavidad Pulpar/metabolismo , Lipopolisacáridos/farmacología , Osteogénesis/fisiología , Tejido Periapical/efectos de los fármacos , Tejido Periapical/metabolismo , Prostaglandina-Endoperóxido Sintasas/fisiología , Animales , Antiinflamatorios no Esteroideos/farmacología , Resorción Ósea/metabolismo , Celecoxib/farmacología , Ciclooxigenasa 2/análisis , Escherichia coli/metabolismo , Expresión Génica , Indometacina/farmacología , Lipopolisacáridos/análisis , Masculino , Ratones Endogámicos C57BL , Osteogénesis/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/análisis , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Receptores de Prostaglandina E/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Regulación hacia ArribaRESUMEN
BACKGROUND: Most patients with head and neck cancer receive nonsteroidal anti-inflammatory drugs concomitant with oncogenic treatment in order to control cardiovascular diseases and chronic inflammatory processes. Inflammation is closely related to neoplastic development and the release of inflammatory cytokines and chemokines represents a crucial event in this relationship. The aim of the present study was to evaluate the effect of acetylsalicylic acid (ASA) and celecoxib treatment in the gene expression pattern of cytokines and chemokines in squamous cell carcinoma (OSCC) cell lines. MATERIALS AND METHODS: Cells were treated with plasmatic concentrations of ASA and celecoxib and were submitted to cell viability assay and immunoenzymatic assay to investigate interleukin 6 (IL6) production. Treated cells were collected and a gene expression array was performed using the reverse transcriptase-quantitative polymerase chain reaction. RESULTS: Both treatments provoked a discrete inhibitory effect on cell viability and modulated IL6 production. The mRNA expression of several cytokines, chemokines, chemokine receptors, and other chemotaxis-related genes were modulated after treatment with ASA and celecoxib. CONCLUSION: Plasmatic doses of ASA and celecoxib altered the expression of IL6 and the gene expression of chemokines (ligands and receptors) and cytokines in a dose- and time-dependent manner.
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Antiinflamatorios no Esteroideos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Interleucina-6/genética , Neoplasias de la Boca/tratamiento farmacológico , Aspirina/farmacología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Celecoxib/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quimiocinas/genética , Citocinas/genética , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/tratamiento farmacológico , Neoplasias de la Boca/genética , Neoplasias de la Boca/patologíaRESUMEN
In spite of the high incidence of breast cancer worldwide, there are few strategies for its chemoprevention, and they have limited adherence mainly due to their serious adverse effects. As a new approach for local breast cancer chemoprevention, we developed and optimized microemulsions for topical delivery of celecoxib to the breast skin, and evaluated their combination with microneedles to improve drug penetration for localization in the mammary tissue. Microemulsions containing water at 15% (ME-15), 29% (ME-29) and 60% (ME-60) were obtained and characterized. They were isotropic, displayed Newtonian behavior and particle size smaller than 100â¯nm. ME-15 and ME-29 increased transepidermal water loss (TEWL) compared to ME-60, and displayed stronger vascular toxicity, evidenced by hemorrhage and lysis in HET-CAM assays. ME-60 was more efficacious at increasing celecoxib cutaneous and percutaneous delivery (1.3-4-fold). Increasing the number of microneedle roller applications from 1 to 8 increased the number of skin punctures and TEWL; its association with ME-60 promoted no further increase in TEWL, but improved (1.6-4-fold) celecoxib cutaneous and percutaneous delivery. Microemulsion incorporation reduced celecoxib IC50 in MCF-7 cells (3.3-fold), suggesting that presence of formulation components in the mammary tissue might improve drug cytotoxicity.